Novel 3,6-unsymmetrically disubstituted-1,2,4,5-tetrazines: S-induced one-pot synthesis, properties and theoretical study

Li, Chen; Ge, Haixia; Yin, Bing; She, Mengyao; Liu, Ping; Li, Xiangdong; Li, Jianli

doi:10.1039/c4ra10808f

Cited by 23 publications

(18 citation statements)

References 73 publications

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“…40,41 Similarly, decreasing the electron density of the tetrazine ring by substituting positions C3 and C6 with aromatic heterocycles with different pendant EWGs increases the reaction rate against dienophiles. 42,43 The electronic effect of the number of N-heteroatoms in the heterocyclic ring was also studied by Sauer et al 44 The authors showed that tetrazine reacts significantly faster than, for example, triazine (K 2 tetrazine 4 K 2 triazine 4 K 2 pyridazine 4 K 2 pyridine; Fig. 5b).…”

Section: Features For Reactivity Of Iedda Reactantsmentioning

confidence: 93%

“…75,76 Sulphur is described to react first with hydrazine to give NH 2 NHSH, which serves as an active nucleophile towards nitriles, generating a reactive intermediate that eliminates H 2 S to form the dihydrotetrazine core. 43,75,77 Importantly, although these conditions have been successfully used for the synthesis of aromatic tetrazines, very low yields are reported in the case of alkyl tetrazines. Alternatively, N-acetylcysteine was successfully tested as catalyst for the synthesis of tetrazines possibly through the formation of amidrazone intermediates.…”

Section: Synthesis Of Tetrazine Derivativesmentioning

confidence: 99%

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Inverse electron demand Diels–Alder reactions in chemical biology

2017

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The emerging inverse electron demand Diels-Alder (IEDDA) reaction stands out from other bioorthogonal reactions by virtue of its unmatchable kinetics, excellent orthogonality and biocompatibility. With the recent discovery of novel dienophiles and optimal tetrazine coupling partners, attention has now been turned to the use of IEDDA approaches in basic biology, imaging and therapeutics. Here we review this bioorthogonal reaction and its promising applications for live cell and animal studies. We first discuss the key factors that contribute to the fast IEDDA kinetics and describe the most recent advances in the synthesis of tetrazine and dienophile coupling partners. Both coupling partners have been incorporated into proteins for tracking and imaging by use of fluorogenic tetrazines that become strongly fluorescent upon reaction. Selected notable examples of such applications are presented. The exceptional fast kinetics of this catalyst-free reaction, even using low concentrations of coupling partners, make it amenable for in vivo radiolabelling using pretargeting methodologies, which are also discussed. Finally, IEDDA reactions have recently found use in bioorthogonal decaging to activate proteins or drugs in gain-of-function strategies. We conclude by showing applications of the IEDDA reaction in the construction of biomaterials that are used for drug delivery and multimodal imaging, among others. The use and utility of the IEDDA reaction is interdisciplinary and promises to revolutionize chemical biology, radiochemistry and materials science.

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Section: Features For Reactivity Of Iedda Reactantsmentioning

confidence: 93%

Section: Synthesis Of Tetrazine Derivativesmentioning

confidence: 99%

Inverse electron demand Diels–Alder reactions in chemical biology

2017

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“…The Ph substituent as R 2 induces the bathochromic shift of λ ex (Entries 1–6 and 13–16, Table 3 ) in comparison to n -Bu (Entries 7–12 and 17–20, Table 3 , red color vs. blue color in Figure S65 ). In the case of the 15a – h series, which consists of the symmetrically substituted compounds, the λ em increases together with the rising electron-donating strength of R 1 (H < t -Bu < OCH 3 ), which is typical for tetrazine derivatives [ 34 , 35 ]. A partially similar relationship is observed in the unsymmetrically substituted 10a – l series.…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Luminescent Properties of s-Tetrazine Derivatives Conjugated with the 4H-1,2,4-Triazole Ring

2022

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New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.

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“…The iEDDA reaction is driven by the electrophilicity of the tetrazine, coupled with the high exothermicity of the reaction with the strained alkene . Faster kinetics can be achieved by increasing the strain of the TCO by adding cis ‐cyclopropane or increasing the electron deficiency of the tetrazine . However, the biological potential of this reaction is limited by size, aqueous stability and ease of synthesis of both the tetrazine and TCO, thus underscoring the importance of accessibility and practicality as equally important considerations to that of speed (Scheme ).…”

Section: Methodsmentioning

confidence: 99%

Cycloadditions of Trans‐Cyclooctenes and Nitrones as Tools for Bioorthogonal Labelling

et al. 2019

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Trans‐cyclooctenes (TCOs) represent interesting and highly reactive dipolarophiles for organic transformations including bioorthogonal chemistry. Herein we show that TCOs react rapidly with nitrones and that these reactions are bioorthogonal. Kinetic analysis of acyclic and cyclic nitrones with strained‐trans‐cyclooctene (s‐TCO) shows fast reactivity and demonstrates the utility of this cycloaddition reaction for bioorthogonal labelling. Labelling of the bacterial peptidoglycan layer with unnatural d‐amino acids tagged with nitrones and s‐TCO‐Alexa488 is demonstrated. These new findings expand the bioorthogonal toolbox, and allow TCO reagents to be used in bioorthogonal applications beyond tetrazine ligations for the first time and open up new avenues for bioorthogonal ligations with diverse nitrone reactants.

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Novel 3,6-unsymmetrically disubstituted-1,2,4,5-tetrazines: S-induced one-pot synthesis, properties and theoretical study

Abstract: 18 unprecedented 3,6-unsymmetrically disubstituted-1,2,4,5-tetrazines were synthesized, and their spectral and electrochemical properties are studied. A systematic theoretical investigation based on DFT calculations was carried out.

Cited by 23 publications

References 73 publications

Inverse electron demand Diels–Alder reactions in chemical biology

Inverse electron demand Diels–Alder reactions in chemical biology

Synthesis and Luminescent Properties of s-Tetrazine Derivatives Conjugated with the 4H-1,2,4-Triazole Ring

Cycloadditions of Trans‐Cyclooctenes and Nitrones as Tools for Bioorthogonal Labelling

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